Journal
AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY
Volume 304, Issue 11, Pages G970-G979Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpgi.00183.2012
Keywords
Crohn's disease; ulcerative colitis; claudin; tumor necrosis factor-alpha; intestinal barrier; IBD
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Funding
- Friedrich C. Luft Clinical Scientist Pilot Program
- Volkswagen Foundation
- Charite Foundation
- Charite Universitatsmedizin Berlin
- Abbott Immunology (Wiesbaden, Germany)
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Intestinal barrier dysfunction is pivotal in the etiology of inflammatory bowel diseases. Combined clinical and endoscopic remission (mucosal healing) in patients who received anti-TNF-alpha therapies suggests restitution of the intestinal barrier, but the mechanisms involved are largely unknown. We therefore investigated the impact of the anti-TNF-alpha antibody adalimumab on barrier function in two in vitro models. Combined stimulation of Caco-2 and T-84 cells with interferon-gamma and TNF-alpha resulted in a significant decrease of transepithelial electrical resistance (TEER) within 6 h that was prevented by adalimumab in concentrations down to 100 ng/ml. Adalimumab furthermore antagonized the appearance of irregular membrane undulations and prevented internalization of tight junction proteins upon cytokine exposure. In addition, TNF-alpha induced a downregulation of claudin-1, claudin-2, claudin-4, and occludin as well as activation of phosphatidylinositol 3-kinase signaling in T-84 but not Caco-2 cells, which was reversed by adalimumab. At the signaling level, adalimumab prevented increased phosphorylation of myosin light chain as well as activation of p38 MAPK and NF-kappa B accompanying the decline in TEER in both model systems. Pharmacological inhibition of NF-kappa B signaling partially prevented the TNF-alpha induced TEER loss, whereas inhibition of p38 worsened barrier dysfunction in Caco-2 but not T-84 cells. Taken together, these data demonstrate that adalimumab prevents barrier dysfunction induced by TNF-alpha both functionally and structurally as well as at the level of signal transduction. Barrier protection might therefore constitute a novel mechanism how anti-TNF-alpha therapy contributes to epithelial restitution and tissue repair in inflammatory bowel diseases.
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